Preparation of 3-hydroxy-3,6-dimethylhexahydrobenzofuran-2-one and derivatives thereof

ABSTRACT

The present invention relates to the synthesis of intermediate compounds which can be used in the synthesis of mint lactone and related compounds, including 3,6-dimethylhexahydrobenzofuran-2-ones, isomers, and other derivatives.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority benefit under 35 U.S.C. § 119(e) ofU.S. Provisional Patent Application No. 62/217,094, filed on Sep. 11,2015, and U.S. Provisional Patent Application No. 62/259,269, filed Nov.24, 2015. The entire disclosures of each of the aforementioned patentapplications are incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates generally to a process for preparing mintlactone from 3-hydroxy-3,6-dimethylhexahydrobenzofuran-2-one. Moreparticularly, the present invention relates to a process for preparing3-hydroxy-3,6-dimethylhexahydrobenzofuran-2-one from isopulegol andderivatizing 3-hydroxy-3,6-dimethylhexahydrobenzofuran-2-one to producenew and existing organoleptic compounds.

BACKGROUND OF THE INVENTION

Generally, mint lactone is a natural component of mint oil, and apotential precursor to 3,6-dimethylhexahydrobenzofuran-2-one, a valuedflavor and fragrance ingredient. Multiple efforts have been made to costeffectively produce mint lactone, which include the hydrogenation andelimination of hydroxymenthofurolactone (I), which comprises theformula:

as described in Koch (U.S. Pat. No. 6,512,126), and the treatment of3-methylcyclohexanone (II), which comprises the formula:

Compound (II) is treated with methyl pyruvate in a multi-step synthesisinvolving sodium borohydride and iron chloride as described in Xiong (CN102,850,309). While both of these approaches are practicable, they userelatively expensive starting materials and reagents (e.g., Pd/C,NaBH₄). Another major drawback to these methods is that these methods donot produce highly enantio-enriched material. Additional approaches,including the use of citronellal (Shishido, et al., Tetrahedron Letters,33(32), 4589-4592 (1992)), and alkynyl aldehydes (Gao et al., Journal ofOrganic Chemistry, 74(6), 2592 (2009)), have also been described, butagain lack economic feasibility.

Through use of naturally occurring and commercially available isopulegol(III), a key precursor (IV) in the synthesis of mint lactone (V), can beeasily obtained that allows the desired natural stereochemistry to beretained all while using inexpensive and commercially available reagentsas shown in the following equation, Scheme A:

Although isopulegol (III) has been used as a starting material for thesynthesis of enantiopure mint lactone in the past (Chavan et al.,Tetrahedron Letters, 49(29), 6429-6436 (1993)), the approaches appear tohave the common problem of being too costly to be commerciallyattractive, including the use of hydroboration and deprotonation withlithium diisopropyl amide under cryogenic conditions.

As a result of the limitations of these previous approaches, mintlactone and several related materials, such as3,6-dimethylhexahydrobenzofuran-2-one (also known as Koumalactone®) havebeen very expensive to obtain commercially, especially with the desiredstereochemistry, and therefore their use has been limited.

Additionally, specific isomers of mint lactone's saturated analogs canbe difficult to obtain using traditional routes (Gaudin, TetrahedronLetters 56(27), 4769-4776 (2000); Gaudin (U.S. Pat. No. 5,464,824)). Inthis regard, the invention described herein addresses these problems.Particularly, through certain aspects of this invention, compound (IV)can be deoxygenated to generate the desired isomers directly in afacile, high yielding manner.

In view of the disadvantages inherent in the known types of methods nowpresent in the prior art, the present invention provides an improvedmethod to produce mint lactone, derivatives thereof, and relatedmaterials.

SUMMARY OF THE INVENTION

The following discloses a simplified summary of the specification inorder to provide a basic understanding of some aspects of thespecification. This summary is not an extensive overview of thespecification. It is intended to neither identify key or criticalelements of the specification nor delineate the scope of thespecification. Its sole purpose is to disclose some concepts of thespecification in a simplified form as to prelude to the more detaileddescription that is disclosed later.

Described herein are compounds, compositions, and methods of generatingthe compounds thereof, some of which could be useful as a flavor andfragrance ingredient.

According to one aspect of the present invention, a method ofsynthesizing mint lactone (V) is provided, in which isopulegol (III) canbe treated with O₃ to cleave the double bond, followed by quenching withsodium bisulfite—or any suitable quenching agent—to remove peroxide andgenerate 1-(2-hydroxy-4-methyl-cyclohexyl)ethanone (VI). It is notedthat the terms “quenching,” “quench,” or “quenched” as used herein meandecomposing a reactive species in order to stop a reaction and toconvert intermediate products to stable materials which can be isolatedor removed. This hydroxyl ketone (VI) can then be treated with asolution of aqueous sodium cyanide or potassium cyanide, optionally inthe presence of ammonium chloride, to generate a cyanohydrinintermediate that can be hydrolyzed in the presence of a strong aqueousacid, for example concentrated hydrochloric acid, to generateα-hydroxylactone (IV). Other stereoisomers of isopulegol can be used aswell to generate the corresponding versions of compound (IV). Alldownstream chemistries can also be contemplated with stereoisomers ofisopulegol. An example of the reaction can be illustrated by thefollowing equation, Scheme B:

Compound (IV) can then be treated with known conditions to eliminate thealcohol to generate enantiopure mint lactone (Shishido et al.,Tetrahedron Letters, 33(32), 4589-4592 (1992)), and subsequently reducedto generate enantio-enriched 3,6-dimethylhexahydrobenzofuran-2-one.Compound (IV) can also be deoxygenated (e.g., through halogenation andreduction) to generate enantio-enriched3,6-dimethylhexahydrobenzofuran-2-ones. Thus, compound of formula (IV)represents a valuable intermediate for preparing mint lactone.

In another embodiment, compound (IV) can also be derivatized throughesterification or alkylation to make new organoleptic compounds, some ofwhich are described herein.

In another embodiment, mint lactone (V) can also be treated with baseunder catalytic hydrogenation conditions to generate desirable mixturesof isomers. In particular, treatment of mint lactone (V) with base underhydrogenation conditions generates desired isomers (VII) and (VIII), butalso yields desired isomers (IX) and (X), which add very desirableolfactory properties to the mixture.

In this regard, the present invention provides isomers having thefollowing formula:

and/or a compound of formula (VIII)

and/or a compound of formula (IX)

and/or a compound of formula (X)

In another embodiment, compound (IV) can be derivatized at the hydroxylposition to generate new organoleptic compounds (XI)

and (XII).

In this regard, compounds (XI) and (XII) are derived from3-hydroxy-3,6-dimethylhexahydrobenzofuran-2-one. Compounds (XI) and(XII) comprise a delicate, sweet and creamy odor that is reminiscent ofcoconut and butter. Thus, compounds (XI) and (XII) are used in fragranceand flavoring formulation.

In certain embodiments, compound (IV) is halogenated to provide compound(XIII):

wherein, X is a halogen. This halide intermediate (XIII) can bedehalogenated to provide compounds (VII) and (VIII).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed towards an industrially applicable,economical and advantageous process for the preparation of mint lactone,derivatives thereof, and, related materials. Various modificationsobvious to one skilled in the art are deemed to be within the spirit andscope of the present invention.

The word “exemplary” is used herein to mean serving as an example,instance, or illustration. Any aspect or design described herein as“exemplary” is not necessarily to be construed as preferred oradvantageous over other aspects or designs. Rather, use of the wordexemplary is intended to disclose concepts in a concrete fashion. Asused in this application, the term “or” is intended to mean an inclusive“or” rather than an exclusive “or.” The articles “a” and “an” as used inthis application and the appended claims should generally be construedto mean “one or more” or “at least one” unless specified otherwise orclear from context to be directed to a singular form. Additionally, theterms “formula,” “compound,” and “structure” are used interchangeablyunless the context clearly indicates otherwise.

The ozonolysis of isopulegol (III) to obtain hydroxy-ketone (VI) is aknown reaction, which can be done in the presence of water in goodyield. Surprisingly, however, this β-hydroxy ketone does not readilyeliminate to the corresponding enone when treated with a cyanide saltsuch as NaCN or KCN in the presence of ammonium chloride. Rather, thisketone forms a cyanohydrin in good yield at ambient temperature andpressure. Also surprisingly, when in the presence of ammonium chloride,no amino acid forms as one might expect given the likeness toStrecker-type conditions (Strecker, Annalen der Chemie and Pharmazie,91(3), 349-351 (1854)). Further, this cyanohydrin can be readilyhydrolyzed in the presence of aqueous acid, at which point a seeminglysimultaneous intramolecular lactonization occurs to yield compound (IV)as a mixture of stereoisomers with regard to the α-hydroxy position. Itis noted that a phase transfer catalyst is used to facilitate reactionwith a nonaqueous phase during the cyanohydrin formation.

Without wishing to be bound by theory, the reaction proceeds through thecyanide addition to compound (VI) to generate an intermediate describedby structure (XIV) shown in the equation below. This nitrile (XIV) isthen hydrolyzed to the corresponding acid, which may or may not undergosimultaneous intramolecular lactonization to desired compound (IV). Thispathway is depicted in the following equation, Scheme C:

This inventive, nitrile-assisted homologation and lactonization allowsfor the known hydroxy-ketone to be converted to compound (IV) usinginexpensive reagents such as sodium cyanide, potassium cyanide, ammoniumchloride, and hydrochloric acid. Once obtained, compound (IV) can bedehydrated through elimination using reagents such as tosyl chloride,mesyl chloride, thionyl chloride, or phosphorous oxychloride in thepresence of a base, such as pyridine, to afford mint lactone (V). Otherelimination techniques such as heat, strong acid (e.g., H₂SO₄, HBr, HCl,HI), and radical assisted deoxygenation can also be employed.

Additionally, compound (V) can be reduced to3,6-dimethylhexahydrobenzofuran-2-one using any number of enonereduction techniques, such as hydrogenation in the presence of acatalyst (e.g., Pd, Ru, Ni, Rh, Cu, etc.) hydride reduction usinghydride reducing agent (e.g., lithium aluminum hydride, sodiumborohydride, diisopropyl aluminum hydride, sodiumbis(2-methoxyethoxy)aluminumhydride available under the trade nameRed-Al®) or enzymatic reduction. It is noted that the term“hydrogenation” as used herein means a reduction reaction whereinhydrogen is the reducing agent.

It should be noted that hydrogenation in the presence of base canunexpectedly offer a desirable mixture of isomers that cannot be easilyobtained through hydrogenation in the absence of base. Specifically,base treatment, such as treatment with sodium methoxide or sodiumhydroxide can result in hydrogenation from the more hindered face ofcompound (V) to result in compounds (VII)

and (VIII),

perhaps through a “ring-opened” intermediate. Unexpectedly, however, thetreatment with base allows some product to be inverted at the hydroxylcarbon position—so called carbon 7a—to result in compound (IX)

and compound (X) as well,

which add a powerful creamy or lactonic quality to the mixture.

Additionally, following compounds having formula (XVI)

and (XVII) are formed.

Table 1 below shows percentages of isometric mixture of3,6-dimethylhexahydrobenzofuran-2-one where Condition A is thehydrogenation of compound (V) in the presence of Raney Nickel at roomtemperature using methanol as a solvent; and Base Treatment is stirringcompound (V) in methanol in the presence of 4.0 eq of sodium methoxideat room temperature for two hours in advance of hydrogenation.

TABLE 1 Compound VII VIII IX X XVI XVII Comments Condition 17.5% 1.2%7.4% 13.6%  47% 6.4% Powerful A with lactonic Base character TreatmentCondition   0%   0%   0% 6.4% 1.4% 87.6% Weak cou- A without marinic/Base lactonic Treatment character

Compound (IV) can also be directly deoxygenated, thereby allowing forthe retention of desired stereochemistry as in compounds (VII) and(VIII). For example, compound (IV) can be halogenated using a reagentsuch as thionyl chloride, PCl₃, POCl₃, HCl, cyanuric chloride, PCl₅,SO₂Cl₂, CCl₄, PBr₃, HBr, HI, or any other suitable halogenating agent.The term “halogenating agent” as used herein means a compound capable ofsubstituting hydrogen atom of an aromatic ring system by halogen atom.The halide intermediate can then be reduced using catalytichydrogenation in the presence of a catalyst (e.g., Pd, Ru, Ni, Rh, Cu)through electrolysis, or through treatment with Zn in a suitable acid,such as acetic acid. These transformations can be carried out stepwise,or in tandem, as shown in Scheme D.

A preferred embodiment of this invention involves the chlorination ofCompound (IV) to generate compound (XVIII) using SOCl₂, or PCl₃, andthen treating the chlorinated product with Zn in acetic acid at elevatedtemperature (70-100° C.) to yield compounds (VII) and (VIII) in highyield and purity. It should be noted that compounds (VII) and (VIII) arehighly sought after fragrance materials that possess a very powerfullactonic and coumarinic type odor. This reaction is shown in Scheme E,below.

Compound (IV) can further be derivatized at the hydroxyl position togenerate new organoleptic compounds. For example, compound (IV) can beacetylated to yield compounds (XI) and (XII) depicted below in Scheme F.The mixture of these products has a delicate, sweet and creamy odor thatis reminiscent of coconut and butter. It is contemplated that otheresters and ethers can also be made that will likely have desirableproperties as well.

Finally, it was observed that the major byproduct formed during thehydro-cyanation and the subsequent hydrolysis was the chiral enone,(XIX), also known as (R)-1-(4-methylcyclohex-1-en-1-yl)ethanone.

Given the purity of this co-product and its potential utility as achiral synthetic intermediate, its production directly from compound(VI) was investigated. It was found that excellent conversions andpurity could be obtained by treating compound (VI) with acid, such asAmberlyst®, and dehydrating compound (VI) at an elevated temperature.This pathway is depicted in Scheme G, below.

EXPERIMENTAL Example 1: Synthesis of Compound (VI) from Compound (III)

Isopulegol (150 g, 0.97 mmol) was combined with H₂O (300 mL) and themixture was cooled to 10° C. in a jacketed glass reactor equipped withan overhead stirrer and gas diffuser. An O₃/O₂ mixture was bubbledthrough the reaction for 5 hours making sure the reaction did not exceed15° C. Following complete consumption of starting material, 121 g ofNaHSO₃ was added at 0° C. and was allowed to warm to room temperatureovernight. The aqueous phase was then extracted with MTBE (350 mL×2),washed with Na₂CO₃ (10% aqueous), and then dried with Na₂SO₄, filtered,and concentrated.

This resulted in 138.7 g of white crystalline solid, 91.3% oftheoretical yield, with an estimated purity of 97.9%. ¹H NMR (CDCl₃, 500MHz), δ 0.87 (d, J=6.5 Hz, 3H, —CH₃), 0.86-0.96 (m, 2H, —CH₂—),1.16-1.25 (m, 1H, —CH₂—), 1.37-1.44 (m, 1H, —CH₃), 1.62-1.67 (m, 1H,—CH₂—), 1.84-1.91 (m, 2H, —CH₂—), 2.10 (s, 3H, —CH₃), 2.22-2.27 (m, 1H,—CH—), 3.00 (s, broad, 1H, —OH), 3.71-3.76 (m, 1H, —CHO—).

Example 2: Synthesis of Compound (IV) from Compound (VI)

31.2 g (20 mmol) of hydroxy-ketone II, methyl t-butyl ether (100 mL),tetrabutylammonium hydrogensulfate (0.1 g), and saturated aqueous NH₄Cl(150 mL) were placed into a 500 mL three-necked round-bottom flaskequipped with a thermometer and a 250 mL addition funnel. The apparatuswas assembled in a well-ventilated hood and the flask was surrounded byan ice-bath. A solution of NaCN (19.8 g, 40 mmol) in water (100 mL) wasadded drop wise through the addition funnel, making sure the temperaturewas kept under 15° C. The reaction was kept stirring for another 2 hoursat this condition. Methyl t-butyl ether (100 mL) and water (100 mL) wereadded to the reaction mixture, and the mixture was transferred into aseparation funnel and the aqueous layer was removed.

The organic layer was again washed with water (100 mL). The organiclayer was then evaporated to yield the crude product as a clear oil. Theproduct was then treated with HCl (35%) at 80° C. to 90° C. for 2 hours.The reaction was then quenched with H₂O (150 mL) and neutralized to pH=5to 6 with aqueous Na₂CO₃ (10%). Methyl t-butyl ether was used to extractthe aqueous mixture (250 mL×2), and the combined organic layers weredried with anhydrous Na₂SO₄, filtered, and evaporated to remove allsolvent. The resulting semi-solid was triturated with heptane (50 mL)and white powder formed immediately.

The liquid phase was decanted and the solid was washed with heptane (50mL) again. The solid was dried under vacuum pressure for 1 hour to givethe product 22.2 g as a white solid. The aqueous phase was treated withferrous sulfate and kept separately as the waste. ¹H-NMR and ¹³C-NMRshowed there were two isomers as the ratio of ˜1:4, which can beseparated further through column chromatograph (Silica gel,EtOAc/Heptane).

Major isomer: ¹H NMR (CDCl₃, 500 MHz), δ 0.92 (d, J=6.5 Hz, 3H, —CH₃),0.95-1.01 (m, 1H, —CH₂—), 1.12-1.22 (m, 2H, —CH₂—), 1.22 (s, 3H, —CH₃),1.46-1.54 (m, 1H, —CH₂—), 1.71-1.74 (m, 1H, —CH₂—), 1.77-1.82 (m, 1H,—CH₂—), 1.84-1.89 (m, 1H, —CH—), 2.11-2.15 (m, 1H, —CH—), 3.72 (td, J=11Hz, J=4.0 Hz, 1H, —CHO—), 3.81 (s, broad, 1H, —OH). ¹³C NMR (125 MHz,CDCl₃) δ 17.5, 21.6, 22.1, 30.9, 33.5, 38.5, 53.4, 74.6, 79.5, 180.3.

Example 3: Synthesis of Compound (V) from Compound (IV)

3.7 g (2 mmol) of hydroxylactone, and pyridine (10 mL) were place into a250 mL three-necked round-bottom flask equipped with a water condenser.Tosyl chloride (5.7 g, 3 mmol) was slowly added as a solid with goodstirring. The reaction was then heated to 120° C. for 10 hours. Thereaction was then cooled down to room temperature and water was added(100 mL), followed by HCl (1N) until the pH=5 to 6. Methyl t-butyl ether(100 mL×2) was used to extract the mixture. The combined organic phaseswere then dried with anhydrous sodium sulfate, filtered, and evaporatedto yield a red liquid as the crude product. Following chromatographypurification (silica gel, EtOAc/Heptane: 5 to 25%), 2 g of product wasobtained as a liquid. ¹H NMR (CDCl₃, 500 MHz), δ 0.90-1.06 (m, 5H, —CH₃,—CH₂—), 1.65-1.74 (m, 1H, —CH₂—), 1.79-1.80 (m, 3H, —CH₃), 1.91-1.95 (m,1H, —CH₂—), 2.18 (td, J=14 Hz, J=5.5 Hz, 1H, —CH₂—), 2.38-2.43 (m, 1H,—CH₂—), 2.78 (dt, J=14 Hz, J=2.5 Hz, 1H, —CH—), 4.60 (dd, J=11 Hz, J=6.0Hz, 1H, —CHO—).

Example 4: Synthesis of Compounds (VII) and (VIII) from Compound (IV)

Step 1: Synthesis of Compound (XVIII) from Compound (IV)

Compound (IV) (36.8 g, 0.2 mol) was dissolved in THF (500 ml) at roomtemperature in a round-bottomed flask and was then treated with SOCl₂(47.6 g, 0.4 mol). The reaction was then brought to reflux. After 20minutes, 20 ml of pyridine was added slowly to the reaction. Thereaction was monitored by GC and TLC for approximately 3 hours until allof the starting material was consumed. The reaction was then cooled toroom temperature and water was slowly added until phase separationoccurred. The organic phase was removed and the aqueous phase wasextracted twice with 200 ml of MTBE. The organic phases were thencombined and treated with aqueous base until the aqueous phase had a pHof 8.

After phase separation, the organic phase was dried with Na₂SO₄,filtered and concentrated to give solid that could then be trituratedwith heptane (3×100 ml) to give 22.0 g of compound (XVI) as an off-whitesolid as the major isomer with ¹H NMR as follows: ¹H NMR (CDCl₃, 500MHz), δ 1.00-1.12 (m, 4H, —CH₂—, —CH₃), 1.18-1.25 (m, 1H, —CH₂—),1.49-1.72 (m, 6H, —CH₂—, —CH₃), 1.72-1.87 (m, 2H, —CH₂—), 2.24-2.27 (m,1H, —CH—), 4.11-4.18 (m, 1H, —CHO—). ¹³C NMR (125 MHz, CDCl₃) δ 21.9,22.9, 23.8, 31.0, 33.4, 37.8, 55.5, 65.6, 80.2, 173.9.

Step 2: Synthesis of Compounds (VII) and (VIII) from Compound (XVIII)

Compound (XVI) (22.0 g, 108.5 mmol) was dissolved in acetic acid (62 ml)and was brought to 80° C. in a round-bottomed flask with magneticstirring. Zinc powder (14 g, 217 mmol) was slowly added to the solution.The reaction was stirred for two hours until GC and TLC showed completeconsumption of starting material. The reaction was then cooled to roomtemperature, diluted with water (200 ml), and extracted with MTBE (2×150ml). The combined organic phases were treated with 10% by wt. aqueousNa₂CO₃ until the aqueous phase was basic. The organic phase wasseparated, dried with Na₂SO₄, filtered and concentrated to give 18.8 gof crude solid. This solid was then crystallized and filtered using coldheptane, resulting in 9.0 g of white crystals of (VII) as the majorisomer and (VIII) as the minor isomer.

The major isomer (˜95%) was obtained with ¹H NMR as follows: ¹H NMR(CDCl₃, 500 MHz), δ 0.97-1.15 (m, 4H, —CH—, —CH₃), 1.13-1.27 (m, 5H,—CH₂—, —CH₃), 1.39-1.47 (m, 1H, —CH₂—), 1.56-1.63 (m, 1H, —CH₂—),1.76-1.79 (m, 1H, —CH₂—), 1.88-1.91 (m, 1H, —CH—), 2.17-2.25 (m, 2H,—CH₂—), 3.69-3.75 (m, 1H, —CHO—). ¹³C NMR (125 MHz, CDCl₃) δ 12.4, 21.9,26.6, 31.3, 34.1, 38.2, 41.3, 51.4, 82.3, 179.3.

Example 5: Synthesis of Compounds (XI) and (XII) from Compound (IV)

Compound (IV) (5 g, 27 mmol) was combined with N,N-dimethylaminopyridine(DMAP) (0.33 g, 2.7 mmol) and 100 mL of tetrahydrofuran (THF) in a roundbottom flask placed in an ice bath equipped with a magnetic stirrer andrubber septum. Acetic anhydride (4.2 mL, 44 mmol) was added drop wiseusing a syringe. When the reaction was complete by GC FID analysis, 0.8mL of H₂O was added to quench any remaining anhydride, and then anadditional 10 mL H₂O was added. The THF was then removed from themixture using a rotary evaporator, and the 10% aqueous Na₂CO₃ was addeduntil the pH=8. The aqueous mixture was then extracted with ethylacetate, and the organic layer was dried with anhydrous sodium sulfate,filtered, and concentrated to give 5.9 g of organic residue.

This residue was then purified using silica chromatography. A solventsystem of 8 to 15% ethyl acetate in heptane was used as eluent, and thetwo major products were obtained.

One product was obtained as the major isomer with ¹H NMR as follows: ¹HNMR (CDCl₃, 500 MHz), δ 1.01 (d, J=6.5 Hz, 3H, —CH₃), 1.01-1.08 (m, 1H,—CH₂—), 1.26-1.40 (m, 2H, —CH₂—), 1.41 (s, 3H, —CH₃), 1.55-1.61 (m, 1H,—CH₂—), 1.79-1.88 (m, 2H, —CH₂—), 2.08 (s, 3H, —CH₃), 2.25 (dt, J=11 Hz,J=1.0 Hz, 1H, —CH—), 2.65-2.70 (m, 1H, —CH—), 3.78 (td, J=11 Hz, J=3.5Hz, 1H, —CHO—).

Example 6: Synthesis of Compound (XIX) from Compound (VI)

230 g (1.47 mol) of compound (VI) was dissolved in 500 ml of Toluene,charged with 4.6 g of Amberlyst® 15 catalyst, and was placed in a roundbottomed flask equipped with a Dean Stark apparatus for removal ofwater. The mixture was heated at 80-140° C., including all ranges andsubranges therebetween, and more preferably, at 110-130° C. for 7 hoursuntil all water had appeared to stop forming. In some embodiments,dehydration was performed continuously. The Amberlyst® was then filteredout and the toluene was removed. The isolated residue was then distilledat around 1.0 mbar and 65-70° C. (42-48° C. head temperature) to obtain173.2 g of >97% pure desired product,(R)-1-(4-methylcyclohex-1-en-1-yl)ethanone (i.e., compound (XIX)): ¹HNMR (CDCl₃, 500 MHz), δ 0.97 (d, J=6.5 Hz, 3H, —CH₃), 1.13-1.21 (m, 1H,—CH₂—), 1.61-1.67 (m, 1H, —CH₂—), 1.80-1.88 (m, 1H, —CH₂—), 2.05-2.14(m, 1H, —CH₂—), 2.27 (s, 3H, —CH₃), 2.30-2.45 (m, 2H, —CH₂—), 6.85 (m,1H, —CH═C).

The second, minor isomer was obtained with ¹H NMR as follows: ¹H NMR(CDCl₃, 500 MHz), δ 1.02 (d, J=6.5 Hz, 3H, —CH₃), 1.00-1.08 (m, 1H,—CH₂—), 1.13-1.20 (m, 1H, —CH₂—), 1.28-1.36 (m, 1H, —CH₂—), 1.61 (s, 3H,—CH₃), 1.57-1.63 (m, 2H, —CH₂—), 1.82-1.86 (m, 1H, —CH₂—), 1.89-1.93 (m,1H, —CH—), 2.06 (s, 3H, —CH₃), 2.24-2.28 (m, 1H, —CH—), 4.13-4.19 (m,1H, —CHO—).

It is therefore submitted that the instant invention has been shown anddescribed in what is considered to be the most practical and preferredembodiments. It is recognized, however, that departures may be madewithin the scope of the invention and that obvious modifications willoccur to a person skilled in the art. With respect to the abovedescription then, it is to be realized that the optimum dimensionalrelationships for the parts of the invention, to include variations insize, materials, shape, form, function and manner of operation, assemblyand use, are deemed readily apparent and obvious to one skilled in theart, and all equivalent relationships to those illustrated in thedrawings and described in the specification are intended to beencompassed by the present invention.

Therefore, the foregoing is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will readily occur to those skilled in the art, it is notdesired to limit the invention to the exact construction and operationshown and described, and accordingly, all suitable modifications andequivalents may be resorted to, falling within the scope of theinvention.

1. A method of producing an α-hydroxylactone, comprising the steps of:(a) forming a cyanohydrin intermediate from a hydroxy-ketone viacyanohydrin formation, wherein said cyanohydrin intermediate comprises anitrile; and (b) hydrolyzing and lactonizing said nitrile of saidcyanohydrin intermediate in the presence of an aqueous acid to generatean α-hydroxylactone, wherein said α-hydroxylactone is3-hydroxy-3,6-dimethylhexahydrobenzofuran-2-one.
 2. The method of claim1, wherein said hydroxy-ketone comprises1-(2-hydroxy-4-methyl-cyclohexyl)ethanone).
 3. The method of claim 1,wherein said cyanohydrin formation is performed using an aqueous mixtureof a cyanide salt in the presence of ammonium chloride.
 4. The method ofclaim 3, wherein said cyanide salt comprises sodium cyanide or potassiumcyanide.
 5. The method of claim 3, wherein a phase transfer catalyst isused to facilitate reaction with a nonaqueous phase during saidcyanohydrin formation.
 6. The method of claim 1, wherein the step ofhydrolyzing said cyanohydrin intermediate is performed using a strongaqueous acid, wherein said aqueous acid comprises concentratedhydrochloric acid.
 7. An organoleptic compound chosen from formula (I)and formula (II) below:

optionally substituted derivatives thereof, and isomers thereof, whereinsaid organoleptic compound of formula (I) and formula (II) is derivedfrom 3-hydroxy-3,6-dimethylhexahydrobenzofuran-2-one.
 8. The compound ofclaim 7, wherein said organoleptic compound of formula (I) and formula(II) is used for enhancing a fragrance formulation.
 9. The compound ofclaim 7, wherein said organoleptic compound of formula (I) and formula(II) is used for enhancing a flavoring formulation.
 10. A compound ofgeneral formula (III) below and/or an isomer thereof of formula (I)below and/or a polymeric derivative thereof:

wherein X is halogen, further wherein said compound is derived from anα-hydroxylactone.
 11. The compound of claim 10, wherein said X ischlorine.
 12. A method of producing organoleptic compounds, comprisingthe steps of: (a) providing an α-hydroxylactone compound having thefollowing formula (IV):

(b) deoxygenating said α-hydroxylactone compound.
 13. The method ofclaim 12, wherein said α-hydroxylactone compound is halogenated using ahalogenating agent and then reduced to generate one or both of theisomers having the following formulas (V) and (VI):


14. The method of claim 13, wherein said α-hydroxylactone compound isdeoxygenated via chlorination followed by reduction with zinc inpresence of an acid.
 15. The method of claim 14, wherein said acid isacetic acid.
 16. The method of claim 14, wherein said chlorination isperformed with thinoyl chloride or phosphorus trichloride.
 17. A methodof producing isomers or derivatives of a compound having the followingformula (VII):

(a) hydrogenating said compound in the presence of a base to obtain amixture of isomers enriched with isomers comprising following formulas(VIII) through (XI):


18. The method of claim 17, wherein said base is introduced to saidcompound in advance of hydrogenation to promote ring-opening andisomerization.
 19. An organoleptic composition, comprising: isomeric3,6-dimethylhexahydrobenzofuran-2-one having at least 20% of acombination of isomers having following formulas (XII) and (XIII),


20. A method of producing (R)-1-(4-methylcyclohex-1-en-1-yl)ethanone,comprising the steps of: (a) providing a compound having the generalformula (XIV):

(b) dehydrating said compound.
 21. The method of claim 20, wherein saiddehydration is catalyzed by an acid.
 22. The method of claim 21, whereinsaid acid is a cationic resin.
 23. The method of claim 21, wherein saiddehydration is performed continuously.
 24. The method of claim 21,wherein said dehydration is performed at an elevated temperature. 25.The method of claim 24, wherein said temperature is between 80° C. and140° C.
 26. A method of producing mint lactone, comprising the steps of:(a) providing an α-hydroxylactone of general formula (XV):

(b) eliminating the hydroxyl group of said α-hydroxylactone.
 27. Themethod of claim 26, wherein the step of eliminating the hydroxyl groupis performed by halogenating said α-hydroxylactone, and eliminating thehalogen.
 28. The method of claim 26, wherein the step of eliminating thehydroxyl group is performed using a strong acid at an elevatedtemperature.
 29. The method of claim 28, wherein said strong acid is aphosphoric acid.